Hemophilia Group Research Articles

Pharmacokinetics of Efmoroctocog alfa by Two-Compartment Model Highlights Hemophilia A Patients with Biphasic Decay, Long Mean Residence Time, and Beta Half-Life.

Background/Objectives: A compartmental pharmacokinetics (PK) analysis of new extended half-life FVIII concentrates has never been performed in a large cohort of hemophilia patients. An improved PK analysis of individual outcomes may help to tailor hemophilia replacement treatment. Methods: PK outcomes after the infusion of a standard single dose of Efmoroctocog alfa were collected from 173 patients with severe/moderately severe hemophilia A in 11 Italian hemophilia centers. Factor VIII clotting activity (FVIII:C) was measured by one-stage clotting assay (OSA) in all patients, and chromogenic substrate assay (CSA) in a subgroup (n = 52). Fifty patients underwent a comparative PK assessment with standard half-life (SHL) recombinant FVIII (rFVIII) products. Non-compartmental analysis (NCA), one compartment model (OCM), and TCM were used to analyze the decay curves of all patients, and one-way paired ANOVA to compare the PK outcomes. Results: All 173 PKs conformed to the NCA and OCM, but only 106 (61%) conformed to the TCM based on the biphasic features of their decay curves. According to the TCM, the Beta HL and MRT of rFVIIIFc were 20.42 ± 7.73 and 25.64 ± 7.61 h, respectively. ANOVA analysis of the outcomes from the three PK models showed significant differences in clearance, half-life (HL), and mean residence time (MRT) (p < 0.001 for all parameters). As anticipated, the HL and MRT of rFVIIIFc were longer than those of SHL rFVIII. Comparing OSA with CSA outcomes, Cmax resulted higher when measured by CSA (p = 0.05) and, according to TCM, Beta HL resulted longer when measured by OSA (p = 0.03). FVIII:C trough levels obtained with SHL concentrates were significantly lower than those obtained with rFVIIIFc at each post-infusion time point. Conclusions: In a large group of hemophilia A (HA) patients, three different PK models confirmed the improved pharmacokinetic (PK) characteristics of rFVIIIFc, compared with standard half-life rFVIII concentrates. The TCM only fits two-thirds of the PKs, highlighting their biphasic decay and a long Beta half-life. In these patients, the TCM would be preferable to properly evaluate individual PK features.

Assessment of jaw bone mineral density, resorption rates, and oral health in patients with severe hemophilia: a case-control study.

Knowledge about oral hygiene, gingival bleeding, mineral density, and resorption of jaw bones in patients with hemophilia is limited. We evaluated the periodontal and bone status in such patients. Material and methods: Forty-eight patients with severe type A/B hemophilia and 49 age- and sex-matched controls were included. Assessments included simplified oral hygiene index (OHI-S), calculus index, debris index, gingival index (GI), gingival bleeding time index (GBTI), and decayed, missing, and filled teeth index (DMFTI). Bone resorption was evaluated using panoramic mandibular index (PMI), mental index (MI), and alveolar crest ratio (ACR). Mineral density in the condyle, angulus, and premolar areas was assessed using fractal analysis, with fractal dimensions denoted as condyle fractal dimension (CFD) for the condyle, angulus fractal dimension (AFD) for angulus, and premolar fractal dimension (PFD) for premolar region. The mean scores were DMFTI = 11.77, OHI-S = 2.44, PMI = 0.268, MI = 5.822, GI = 3.02, GBTI = 2.64, ACR = 2.06, CFD = 1.31, AFD = 1.31, and PFD = 1.17 in the hemophilia group and DMFTI = 11.449, PMI = 0.494, MI = 7.43, GI = 0.67, GBTI = 0.98, OHI-S = 1.45, ACR = 2.87, CFD = 1.35, AFD = 1.35, and PDF = 1.23 in the control group. Differences were significant for all parameters (p < 0.005) except for the DMFTI index. Conclusions: Because of poor oral hygiene, high bone resorption, and low bone mineral density in these patients, clinicians should consider potential bone changes when planning to treat these patients.

Morphological analysis of patellofemoral joint in haemophilic arthropathy: A case-control study.

Knees affected by haemophilic arthropathy exhibit distinct differences in both bone morphology and soft tissue behaviour. This study aims to analyse the morphological characteristics of the distal femur and patellofemoral joint in patients with haemophilia in comparison to normal healthy population. Study was conducted as pair-matched case-control study with 43 individuals in both the haemophilia group and the control group. Patellar luxation, patellar tilt (PT), length of the patella in both axis (pAP, pML), depth and angle of trochlear sulcus (SD, SA), lateral trochlear inclination (LTI), medial and lateral femoral facet length (mFL, LFL), intercondylar depth (ID), transepicondylar axis (TEA) and lateral condyle length (LCL) were assessed on knee MRI. Correlation between Pettersson score and measured variables were also analysed. PT was medial sided in 10 (23.2%) cases in haemophilic group. Mean values of pAP, pML, PT were significantly lower in haemophilia group (p<.001, p: .007, p=.001 respectively). There were no significant changes in SA (p=.628), SD (p=.340), LTI (p=.685), LFL (p=.241) and MFC-LFC (p=.770) whilst mFL was significantly longer in haemophilia group (p=.009). ID (p<.001), TEA (p=.007) and LCL (p=.001) were all shorter in haemophilia group. Pettersson score was inversely correlated with pAP, pML, ID, TEA, LCL, pML/SA and ID/LCL. Morphological changes in haemophilic arthropathy involve a smaller and medially-tilted patella, narrowed lateral condyle and transepicondylar axis, combined with reduced intercondylar depth. These alterations must keep in mind especially in pre- and intraoperative assessments for arthroplasty procedures.

Molecular genetic diagnosis in the group of hemophilia A patients in Belarus: 12 new allelic variants in the &lt;i&gt;F8&lt;/i&gt; gene

Hemophilia A is the most common severe bleeding disorder caused by various genetic changes in the F8 gene, leading to coagulation factor VIII deficiency. Hemophilia A is characterized by high heterogeneity of genetic defects. The severity of hemophilia A varies depending on the type of genetic defects in the F8 gene. More than 3000 unique variants of the F8 gene are associated with the hemophilia A. Approximately 30% of genetic defects occur de novo. The aim of this study is to determine the spectrum of genetic defects in the F8 gene in children with hemophilia A in Belarus. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). The study included 98 patients with hemophilia A, who had been treated or followed up at the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). Patients were categorized into 3 groups based on the severity of their disease: severe (n = 82), moderate (n = 3), and mild (n = 13). Twenty (20.4%) patients had a history of inhibitors to factor VIII. For our study, we used venous blood samples. Genomic DNA was isolated from leukocyte suspension (obtained from the whole blood samples) using phenol-chloroform extraction. All severe hemophilia A patients were prescreened for intron 22 and 1 inversions in the F8 gene using inverse and multiplex polymerase chain reaction assays, respectively. Sequencing of F8 coding regions was carried out by next generation sequencing. All clinically relevant variants were confirmed by Sanger sequencing. Genetic testing revealed that 99% of the patients with hemophilia A (n = 97) had pathogenic variants in the F8 gene. Intron 22 and intron 1 inversion mutations within the F8 gene were detected in 45.1% (n = 37) and 1.2% (n = 1) patients with severe hemophilia A, respectively. Two patients had an abnormal pattern of intron 1 inversion, not previously described in the literature. A total of 48 different variants in the F8 gene were detected in 57 patients using next generation sequencing. Eleven of the 48 genetic variants identified have not been previously reported.

Co-administration of FVIII with IVIG reduces immune response to FVIII in hemophilia A mice

Hemophilia A is an X-linked recessive congenital bleeding disorder. Exogenous infusion of FVIII is the treatment of choice, and the development of immunoglobulins against FVIII (inhibitors) remains the major challenge in clinical management of the disease. Here, we investigated the effect of co-administration of FVIII with intravenous immunoglobulin (IVIG) on the development of inhibitors in previously untreated hemophilia A mice. A group of hemophilia A mice (C57BL/6FVIII−/−) received weekly injections of recombinant human FVIII (rFVIII) for twelve consecutive weeks while a second group received co-injections of rFVIII + IVIG. An in-house enzyme-linked immunosorbent assay (ELISA) was designed to detect antibodies to rFVIII. Every mouse in the first group developed antibodies to rFVIII. In contrast, mice treated with rFVIII + IVIG showed significantly lower antibody titers. Interestingly, when co-administration of IVIG was discontinued after 12 weeks in some mice (rFVIII continued), these mice experienced an increase in antibody titer. In contrast, mice that continued to receive rFVIII + IVIG retained significantly lower titers. In conclusion, prophylactic rFVIII co-administration with IVIG modulated the immune response to FVIII and resulted in decreased anti-FVIII antibody titer. These findings suggest that co-injection therapy with IVIG could potentially be effective in the management of hemophilia A patients at risk of inhibitor development.

Phenotypic variation in severe hemophilia A is related to endogenous thrombin potential and plasma levels of factor VII.

Hemophilia A is a bleeding disorder caused by deficiency or low activity of circulating factor VIII characterized by prolonged blood coagulation time and often spontaneous bleeding. Patients with the severe form of the disease may present considerable heterogeneity in the occurrence of bleeding episodes and some of them have a mild hemophilia A phenotype. This study aimed to evaluate the association of biomarkers and coagulation parameters to the differential hemorrhagic profile of severe hemophilia A patients. Polymorphisms in the genes of proteins C and S, factors V and VII and prothrombin were evaluated in a group of severe hemophilia A patients with a broad spectrum of bleeding profile. Plasma levels of coagulation factors and thrombin generation were also analyzed. This study included 59 Brazilian hemophilia A patients who were allocated into low bleeding profile (LBP; n = 33) and high bleeding profile (HBP; n = 26) groups based on their joint and muscle bleeding episodes requiring treatment in the 5 years before inclusion in the study. Results evidenced that endogenous thrombin potential (ETP) and plasma factor VII levels were significantly higher in the LBP group. Results indicate a prominent importance of FVII plasma activity and endogenous thrombin potential on the differential bleeding phenotype of hemophilia A patients.

Impact of Depression on Patients With Hemophilia: A Retrospective Case-Control Research

BackgroundHemophilia is an inherited recessive hemorrhagic disorder of the X-linked type, suffered by the male sex. Adults with hemophilia are coping with numerous diagnostics, associated comorbidities, pain, and difficult gait by arthropathy in ankles and feet. Physical pains contribute to depression in patients with hemophilia.PurposeThe study aimed to assess the impact of depression in adult patient with hemophilia and to compare it with healthy matched-paired controls. Methods: The sample consisted of 100 participants (median age 42.50 ± 30). Patients with hemophilia were recruited from Spanish Hemophiliac Associations (n = 50) and healthy subjects (n = 50) from a Clinic Podiatry Practices (University of Malaga, Spain).ResultsResults and categories of the Spanish-translated version of the Beck Depression Inventory (BDI) were gathered. A clear statistically significant difference (p < 0.001) was presented in the variation of the BDI scores between both groups. Patients with hemophilia presented worse results with a BDI = 7.50 ± 11.25 points compared to healthy subjects with BDI = 2.50 ± 5 points. In the BDI categories, statistically significant differences (p = 0.004) were found in greater BDI categories in the Hemophilia group compared with healthy subjects. Moderate and severe depression categories were only shown in patients with hemophilia.ConclusionsGreater depression scores and range status were observed in patients with hemophilia compared to non-patients with hemophilia. Patients with hemophilia are at increased risk of depressiveness.

Oral Health-Related Quality of Life of Children and Adolescents with Hemophilia

Background: The problems arising from the teeth and the surrounding tissues in patients with hemophilia have an important role in the treatment planning of bleeding disorder. The aim of this study is to evaluate the oral health related quality of life of children and adolescents with hemophilia. Methods: POQL (pediatric oral health related quality of life) Instrument was used in this cross sectional study for quality of life measurement. The instrument was applied to children and adolescents with (n=64) or without (n=196) hemophilia. The data collected were consist of demographic data, POQL and screening part. SPSS 23.0 was used to analyze the data. Results: DMFT and decay (D) scores of patients with hemophilia were higher than the control group: mean values of hemophilia group are 7 and 4.1 vs. control group 4.7 and 2.3 are respectively (p=0.0001 and p=0.011). Among 8-14 age group and teen age group oral health related quality of life scores were significantly higher among hemophilia group, scores were 34.0 and 17.4 in 8-14 group (p=0.0001) and 37.1 and 26.0 in teen group (p=0.043), respectively. Conclusions: DMFT scores and POQL scores have shown that oral health related quality of life of children with hemophilia is worse than healthy controls.

Loss of FVIII Expression by Possible Interlinked Immune and Cellular Stress Response in Hemophilia A Mice Treated with AAV Gene Therapy

Background &#x0D; Hemophilia A is an X-linked genetic disorder caused by a mutation in the gene for factor VIII (FVIII) protein that reduces the ability of blood to clot. Clinical drug trials have shown the potential of adeno-associated virus (AAV) gene therapy as a one-time treatment for hemophilia A that can produce sustained high levels of FVIII. However, a gradual decline in protein levels has been observed in patients after 2-4 years. The hypothesis being tested in the Herzog Lab is that an interlinked immune and cellular stress response could be causing the loss of expression. &#x0D; &#x0D; Methods &#x0D; Two groups of Hemophilia A mice were administered AAV therapy, with one group receiving recurrent doses of Rapamycin. Blood samples were taken at weeks 4, 8, 12 and 14. Mice were euthanized at weeks 4, 8, and 14, and their livers were harvested. qPCR was used to measure AAV copy numbers and FVIII mRNA at 4, 8, and 14 weeks. Cryosections of mice livers from weeks 4, 8, and 14 were stained with antibodies for FVIII protein and CD8. &#x0D; &#x0D; Results &#x0D; qPCR showed roughly half as much AAV copy numbers in the rapamycin group at all time points, and little difference in FVIII mRNA between the groups. There was also a large decrease in AAV copy numbers and FVIII mRNA in both groups between 8 and 14 weeks. Immunohistochemistry showed less CD8 and more FVIII signal in mice treated with rapamycin. &#x0D; &#x0D; Discussion &#x0D; Experiments are currently being performed to investigate the decline in AAV copy numbers and mRNA between weeks 8 and 14. The immunohistochemistry data shows a relationship between increased FVIII protein levels and decreased cellular immune response but does not explain the gradual decline in FVIII. Further investigation into FVIII expression following AAV gene therapy could lead to an effective one-time treatment for hemophilia A. &#x0D;

“OUTCOME ANALYSIS OF TIMELY CONSERVATIVE MANAGEMENT OF HAEMOPHILIC KNEE ARTHROPATHY WITH FACTOR REPLACEMENT AND PHYSIOTHERAPY.”

INTRODUCTION: Haemophilia is a disorder of the initiation of coagulation, and is due to reductions in the concentrations of, or the presence of a less active version of, one of two coagulation factors, factor VIII and factor IX. There are several orthopaedic problems linked to haemophilia including recurrent hemarthroses, chronic synovitis, exion deformities, hypertrophy of the growth epiphyses, damage to the articular cartilage and hemophilic arthropathy MATERIALS AND METHODS : 290 patients of all age group of haemophilia A and B coming to orthopaedic OPD with Knee Haemarthosis between October 2018 to May 2020 were included in our study. These patients were prospectively analyzed for complications and severity. HJHS Scoring system were used to assess the severity of joint disease. RESULTS : . out of 290 patients it was found that haemophilia was more prevalent in rural population (53.10%) as compared to urban population (46.90%). In our study it was found that majority of the patients with haemophilia had single joint involved (57.94%) as compared to 42.06% who had multiple joint involved. It was revealed that in majority right knee was involved (52.41%) followed by left joint in 47.58% patients with haemophilia. It was found that most common complication in patients of knee haemarthrosis was recurrent haemarthrosis (57.24%) followed by synovitis (27.93%). arthropathy (9.31%) . It was found that most common complication in patients of knee haemarthrosis was recurrent haemarthrosis (57.24%) followed by synovitis (27.93%). arthropathy (9.31%) . It was found that out of 290 patients with haemophilia, majority were performing regular physiotherapy (57.59%) followed by 42.41% of the patients who were occasional in physiotherapy. It was found that mean HJHS score was increasing with increasing the severity of the disease. Mean HJHS score for mild cases was 10.53±4.495 as compared to 13.06±7.575 of moderate cases and 17.82±7.991 of severe cases. CONCLUSION In present study haemophilia was more prevalent in rural population. Majority of the patients with haemophilia had single joint and in majority right knee was involved. Most common complication in patients of haemophilia was recurrent haemarthrosis followed by synovitis and arthropathy. Majority of our patients were having severe form of the disease. Adequate factor replacement along with good active physiotherapy early detection and prompt treatment with active life style makes muscles and joints healthier and stronger reduces tendancy of bleeding and further damage of joint. reduce the frequency and longterm complications of knee haemarthrosis like recurrent haemarthosis , synovitis ,arthropathy, fracture and deformity. Prophylactic factor replacement is having denitely positive role as per available literature over western countries, unfortunately it needs more specic clinical trial to know about longterm good results in India.

Increased endoglin levels correlated with angiogenesis-associated angiopoietin-2 in haemophilia patients.

Haemophilia is a bleeding disorder that occurs due to the deficiency of coagulation factors, and the angiogenesis process is an important process underlying the pathophysiology of haemophilic arthropathy. The role of the new adipocytokine endoglin (ENG) in patients with haemophilia is not yet known. The aim of this study is to evaluate the association between ENG protein and angiogenesis-related cytokines in patients with haemophilia for the first time. Plasma protein levels and mRNA expressions of ENG and various angiogenesis-associated cytokines were compared in blood samples collected from 28 patients with haemophilia A or B and 29 healthy volunteers. The relationship between the cytokines and ENG were determined by correlation analysis. Plasma ENG levels and angiogenic markers were found to be significantly higher in patients with haemophilia compared to controls. Real-time PCR studies showed that mRNA expressions of ENG, vascular endothelial growth factor A, hypoxia-inducible factor A, and prostaglandin E2 increased in patients with haemophilia. Correlation analysis showed a significant positive correlation between ENG and angiopoietin-2 levels in the haemophilia group. Besides, a significant decrease in annexin-V binding to platelets in haemophilia patients compared to control was found to be related to the bleeding profiles in the patients. This study determined that ENG protein may be involved in the formation of angiogenesis in haemophilia patients and its effects may be related to angiogenetic marker angiopoietin-2 in this process. Our findings contribute to the literature during the determination of target proteins in haemophilia treatment.

Sexual Health in Patients with Hemophilia; The Insights from the Patient Reported Outcomes, Burdens and Experiences (PROBE) Study

Background: Sexual health in patients with hemophilia (PWH) is inadequately assessed in the routine care. A small survey study in 20 PWH demonstrated that joint stiffness affected their sexual life (53%), patients had joint pain from sexual activity (53%) and patients did not have adequate information regarding sexual activity (Tobase PM et al. Hemophilia 2017). The aim of this study was to evaluate the impact of hemophilia on sexual health in PWH.Methods: The PROBE is a 29-item questionnaire evaluating patient reported outcome in hemophilia. The rationale, development and feasibility of the PROBE was reported previously (Skinner M et al. 2016). We recruited PWH and participants without bleeding disorder in 6 countries. The sexual health was assessed using the question asking whether participants have difficulty with sexual intimacy (yes or no). The logistic regression analysis was used to assessed the association between clinical characteristics and sexual health. The overall health status (PROBE score) was assessed among patients with sexual health problem versus those without.Results: There were 807 respondents (475 had hemophilia A, 76 had hemophilia B and 256 people without bleeding disorder). Median age was 33 years in hemophilia group and 43 years in people without bleeding disorder. Seventy-six percent were male. There was significant greater proportion of people reported difficulty with sexual intimacy among PWH (14.3%) as compared to control (6.25%). Table 1 demonstrated the association between type and severity of hemophilia, bleeding history and joint status and difficulty in sexual intimacy. Patients who bled more than 10 times in the past year, who bled in the past two weeks, who had limit range of motion of any joints and life- or limb-threatening bleeding in the past year were significantly associated with difficulty in sexual intimacy. Multivariate logistic regression revealed that older age, >10 bleeds or life/limb-threatening bleeds in the past year were independent predictors for poor sexual health. Patients who reported difficulty in sexual intimacy has significantly higher total PROBE score, indicating worse general health status comparing to those who did not report (mean score (SD), 4.70 (0.22) vs 3.07 (0.09), P<0.001, Figure 1).Conclusions: The prevalence of difficulty with sexual activity is significantly higher among PWH as compared to general population. Older age, joint bleeding and joint status are related to poor sexual health in PWH. In addition, poor sexual health is strongly associated with worse general health status. Sexual health should be assessed as a routine care in adult PWH. [Display omitted] DisclosuresSkinner:Baxalta, now part of Shire; Bayer; Bioverativ; CSL; Novo Nordisk, Roche and Sobi with administrative support provided by the US National Hemophilia Foundation: Research Funding; Baxalta, now part of Shire; Bayer; Bioverativ; CSL; Novo Nordisk, Roche and Sobi with administrative support provided by the US National Hemophilia Foundation: Research Funding; US National Hemophilia Foundation: Other: non-financial support ; US National Hemophilia Foundation: Other: non-financial support . Curtis:Pfizer: Research Funding; Genentech: Honoraria, Research Funding; Baxter: Research Funding; Bayer: Research Funding, Speakers Bureau; Bioverativ: Research Funding; CSL Behring: Research Funding; Gilead: Honoraria; Novo Nordisk: Honoraria, Research Funding. Nichol:Bayer: Research Funding; CSL Behring: Research Funding; Baxter: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Merck: Consultancy; Bioverativ: Consultancy, Research Funding; Novo Nordisk: Research Funding. Noone:Baxalta, now part of Shire; Bayer; Bioverativ; CSL; Novo Nordisk, Roche and Sobi with administrative support provided by the US National Hemophilia Foundation: Research Funding. O'Mahony:US National Hemophilia Foundation: Other: non-financial support.

Prevalence of Metabolic Syndrome and Risk Factors for Cardiovascular Disease in Hemophilia Patients Compared to a Control Group in South Khorasan, Iran

Background: Hemophilia is a rare inherited sex-linked disease caused by the deficiency or lack of some blood coagulation factors. The severity varies depending on the levels of these factors in the blood. Objectives: Therefore, this study aimed at determining the prevalence of metabolic syndrome and risk factors of cardiovascular disease in patients with hemophilia compared to a control group in 2015. Methods: A case-control study was done on all hemophilia patients referring to the Birjand University of Medical Sciences (n = 91). Healthy subjects with no hemophilia were selected using systematic random sampling from healthy individuals in Birjand City, who were matched in terms of age and sex. The data were entered into SPSS19 software. The significance level of less than 0.05 was considered in this study. Results: The mean age was 34.11 ± 14.68 and 33.72 ± 13.46 years in the case and control groups, respectively. The rate of metabolic syndrome was 12.1% in the control group and 4.4% in the hemophilia group. The results of Mann-Whitney U test showed a significant difference between the two groups in terms of TG (P = 0.016) and LDL (P &lt; 0.001), and the waist circumference was significantly higher (P = 0.001) in the control group than in the hemophilia group. Conclusions: In the present study, the prevalence of metabolic syndrome was significantly lower among hemophilia patients than in the control group. The prevalence of diabetes and hypertriglyceridemia was significantly lower in hemophilia patients than in the control group (healthy subjects).

PRO102 CHARACTERISTICS AND OUTCOMES OF PEDIATRIC HEMOPHILIA-A PATIENTS IN THE INPATIENT SETTING

Hemophilia-A is a rare X-linked genetic blood disorder that deforms the factor VIII clotting protein and reduces the ability for blood to clot. Hemophilia-A affects 1 in 5,000 live male births, with an estimated 20,000 patients living in the United States. There are multiple clinical trials assessing a gene therapy to treat Hemophilia-A. The goal of this study was to characterize pediatric patients with Hemophilia-A and compare them to a simple random sample (SRS) of hospital discharges to characterize the treatable patient population for new gene therapy treatments. The 2016 AHRQ Kids Inpatient Database was used to identify any patient discharge with a primary ICD-10 CM diagnosis of ‘D66’. Hemophilia-A discharges were compared to a SRS of 1000 discharges for patients between the ages of 1 and 20. The two populations were compared on clinical and economic characteristics using t-tests for continuous variables and chi-square for categorical variables. Overall, 468 pediatric Hemophilia-A discharges were analyzed. The average age of hemophilia patients was significantly lower than the SRS (Hem 6.86, SD 6.53 vs SRS 12.85, SD 6.56 p<0.0001). Payer representation was significantly different between the two groups. Specifically, the hemophilia group had a significantly higher rate of Medicaid participation (Hem 62.82% vs SRS 50.8% p<0.0001). Median length of stay was not significantly different between the two groups (Hem 2.5 days vs SRS 3 days p=0.65) however, median charges were significantly different (Hem $57,804 vs SRS $18,731; p<0.0001). Patients with Hemophilia-A do have some differences with the general pediatric inpatient population. Hemophilia patients are younger and require significantly more resources over the same length of stay with a median charge difference of $16,878 per day. This increase in resource utilization is likely tied to the burden of the disease as four of the top five secondary diagnoses were directly associated with Hemophilia.

Myocardial functions, blood pressure changes, and arterial stiffness in children with severe hemophilia A

IntroductionProlonging the life span of patients with hemophilia has led to the emergence of comorbidities. Cardiovascular diseases are one of the important causes of mortality in patients with hemophilia. This study investigated the myocardial functions, blood pressure changes, arterial stiffness, and risk factors associated with cardiovascular diseases in children with hemophilia. Material and methodsIn total, 17 children with severe hemophilia A and 23 healthy children were included in the study. Myocardial functions were evaluated using standard and tissue Doppler echocardiography. Peripheral and central blood pressure measurements were performed, and arterial stiffness was evaluated. Carotid intima–media thicknesses (CIMT) serum glucose, insulin, insulin resistance index, and lipoprotein levels were measured. ResultsThere were no differences between the two groups in terms of age, and biochemical parameters (P > 0.05). The HDL-C levels in the hemophilia group were lower than those in the control group (P < 0.05). Five of the patients had insulin resistance (29.4%), whereas four had low HDL-C levels (23.5%). There were no differences between the groups in terms of the CIMT, peripheral blood pressure, and central systolic blood pressure (P > 0.05). In the hemophilia group, central diastolic blood pressure (cDBP), arterial stiffness, and myocardial performance index were higher (P < 0.05, P = 0.01, P < 0.01), whereas the ejection time was shorter than in the control group (P < 0.05). ConclusionsCompared with the control group, there is an onset of arterial stiffness, cDBP values tend to increase, and serum HDL-C levels are lower in the hemophilia group. Moreover, myocardial systolic functions demonstrate a deterioration that becomes more prominent with the increase in arterial stiffness.

Assessment of self-/parent-reported quality of life in Japanese children with haemophilia using the Japanese version of KIDSCREEN-52.

Assessing health-related quality of life (HRQOL) is critical for providing comprehensive clinical care to patients with haemophilia. HRQOL in individuals with similar cultural backgrounds should be compared using internationally standardized, generic questionnaires. To evaluate self-/parent-assessed HRQOL in Japanese children and adolescents with haemophilia A or B. Children and adolescents aged 8-18years were enrolled. The haemophilia group comprised families with haemophilia, and the control group comprised those without chronic illness. HRQOL was assessed using the self-/parent-reported questionnaire KIDSCREEN-52, the Japanese version. The Oslo 3-Item Social SupportScale was investigated. The questionnaire was completed by 36 families in the haemophilia group and 160 parents and children in the control group. Haemophilia children aged 8-12years had lower scores for 'moods and emotions' than control children; the parents had lower scores in the haemophilia group than in the control group for 'moods and emotions', 'social support and peers', and 'school environment'. No significant differences in HRQOL were observed between both groups of adolescents aged 13-18years or their parents. Neck-shoulder pain was associated with a low psychological state, including 'self-perception', but other joint pains did not affect the outcomes of the HRQOL indices. Social support weaknesses were associated with low physical and psychological states, whereas unexpected hospital visits identified low values for 'self-perception', 'autonomy', and 'school environment'. Proactive mental and clinical care in haemophilia families, especially with young children, will foster a better environment for patients and their parents and ease concerns about progress in haemophilia.

Oral Hygiene and Dentition Status in Patients with Congenital Hemorrhagic Disorders: A Comparative Study

Objective: To compare the status of oral hygiene and dentition in patients with congenital hemorrhagic disorders with their age-matched healthy counterparts. Also, the prevalence of fear of dentists/ dental treatment among these patients was assessed. Material and Methods: This study was performed on children and adults with von Willebrand disease (vWD), hemophilia (A or B), and healthy subjects. Oral health and dentition status was assessed using the simplified oral hygiene index (OHI-S), plaque index, and the decayed, missing, filled teeth (dmft/DMFT) index . One-way ANOVA test was employed to compare the oral hygiene and dentition status of subjects in the three groups. A p-value of 0.05). Higher OHI-S scores and a poor oral hygiene status was observed more in the hemophilia group than the vWD group and healthy controls. A total of 27.3% of the subjects in the vWD group, 18.2% of subjects in the hemophilia group, and no subjects in the healthy group had a fear of dentists or dental treatment . Conclusion: Subjects with vWD had a higher number of carious teeth when compared to the other groups. Poor oral hygiene status was observed in subjects with hemophilia.

The Quality of Life in Children with Hemophilia in Bali

Hemophilia in children adversely affects both their psychological as well as their physical health. It is important to understand more about the quality of life (QoL) in this patient population. The aim of this study was to assess health-related QoL of children with hemophilia in Bali. A cross sectional study was carried out on children with hemophilia in Bali. Data on the quality of life was collected through questionnaires using PedsQL Generic Core Scales version 4.0 inventory. Independent t test was used to analysis data. Child reports showed mean score on each domain function (physical, emotional, social and school function) in hemophilia group compared to healthy children group were 71.8 vs 97.9, 81.4 vs 94.5, 85.0 vs 97.5, and 73.1 vs 94.5, respectively. Parent-proxy reports showed mean scores on each domain function (physical, emotional, social, and school function) in hemophilia group compared to healthy children group were 73.3 vs 97.3, 79.5 vs 94.5, 80.2 vs 97.5, and 67.4 vs 89.8, respectively. Total PedsQL score in hemophilic children and healthy group showed a significant difference in both reports (child report; p<0.05, with the mean difference was -18.7 with 95% CI of -25.9 to -13.6 and parent-proxy report; p<0.05 the mean difference was -19.8 with 95% CI of -25.9 to -13.5). Hemophilia has a negative impact on the children’s daily life. Hemophilia group reported poor quality of life as regards the physical, emotional, social, school functioning domains, and total quality of life than healthy children group.

Incidence and Outcomes of Cardiovascular Disease in Hemophilia Patients: An Analysis of National Inpatient Sample Database

INTRODUCTION Hemophilia A and B are rare X-linked disorders that result in bleeding due to reduced activity of coagulation factor VIII and IX, respectively. With the availability of better medical care and prophylactic treatment modalities, the life expectancy of patients with hemophilia is approaching that of the general population. Patients with hemophilia were initially thought to be protected from cardiovascular disease (CVD) due to hypocoagulable state but this aging population is now known to be at risk for CVD. The primary objective of this study was to determine the incidence of CVD and associated mortality in hospitalized male patients with hemophilia. METHOD: We reviewed National Inpatient Sample (NIS) database from 01/2012 to 09/2015 for admissions due to CVD, defined as acute myocardial infraction (AMI) or ischemic cerebrovascular accident (CVA), as a primary diagnosis using International Classification of Diseases, 9th Revision, and Clinical Modification (ICD-9-CM) codes 410.XX for AMI and 433.XX-437.1 for CVA in males age ≥18 years. Hospitalizations with associated diagnosis of hemophilia A or B were identified using ICD-9CM codes 286.0 or 286.1, respectively. We calculated age-, race- and comorbidities- standardized incidence rate of CVD in hospitalizations with or without associated hemophilia using multivariate logistic regression analysis. Baseline clinical characteristics was also compared between the 2 groups in the overall NIS population. Pearson's Chi-square test and t-test was used to compare categorical and continuous variables, respectively. A propensity score match (PSM) analysis was performed to determine the effect of hemophilia on mortality rate in hospitalizations due to CVD. A trend analysis was done to determine the variation in incidence of CVD over the study period. A p-value ≤0.05 was considered significant. RESULTS: Approximately 50 million (weighted) hospitalizations during the study period were analyzed. A total of 20,845 (0.04%) hospitalizations had associated diagnosis of hemophilia. The baseline clinical characteristics of the overall population is described in table 1. The standardized incidence rate of CVD was significantly lower in hemophilia group 2.9% vs 5.5% (AMI 1.1% vs 2.8% and CVA 1.8% vs 2.7%) compared to non-hemophilia group (p&lt;0.001 for all comparisons). The annual incidence of CVD did not change over the study period in the hemophilia group (trend p=0.906). On PSM analysis, the mortality rate in the CVD associated hospitalizations was not different between the hemophilia and non-hemophilia group, 3.3% vs 4% respectively (OR 0.81 95%CI 0.20-3.3, p=0.772). CONCLUSION: We present a large-scale analysis of CVD incidence and outcomes in hospitalized hemophilia (A or B) patients. Although, CVD and its risk factors are statistically less common in patients with hemophilia compared to general hospitalized population, the incidence is still clinically comparable. Moreover, the CVD associated mortality rate is similar. As patients with hemophilia are at higher risk of CVD treatment related adverse effects, further studies on optimal cardio- prevention and treatment strategies are warranted. Disclosures No relevant conflicts of interest to declare.

Assessment of Bleeding Phenotype in Hemophilia Α By a Novel Point-of-Care Global Assay

Introduction: Patients with Hemophilia A have considerable phenotypic heterogeneity with respect to clinical severity based on their baseline factor levels. As clinical bleeding risk is helpful to individualize factor replacement therapy in hemophilia patients, previous studies have utilized direct and indirect methods of thrombin generation to classify individual bleeding phenotypes, however, with variable results. An easy to use, point-of-care, global assay to assess bleed phenotype, can be a useful tool in the clinical setting to determine intensity of prophylaxis therapy for patients with hemophilia. We have previously introduced a novel, point-of-care (POC), dielectric microsensor, ClotChip, and demonstrated its sensitivity to factor replacement in patients with severe hemophilia A. We aim to further test the ability of ClotChip in assessment of a bleeding phenotype, as described by a bleeding score, in patients with hemophilia A. Methods: After IRB approval, 28 patients with hemophilia A of varying severity and well-characterized bleeding history, were enrolled in this study at the time of trough factor levels. The bleeding history was extracted from patient charts and included number of bleeds (joint and soft-tissue), annual factor usage in terms of units/kg, and number of target joints. These parameters were used to generate a bleeding score (range: 0 - 24), and patients were divided in to 2 categories with scores between 0 - 12 (n=14) and &gt; 12 (n=14). Healthy volunteers (n=17) were accrued as controls. Whole blood samples were obtained by venipuncture into collection tubes containing 3.2% sodium citrate. Samples were then tested with the ClotChip within 2 hours of collection. ClotChip is based on the electrical technique of dielectric spectroscopy (DS) and features a low-cost (material cost &lt; $1), small- sized (26mm × 9mm × 3mm), and disposable microfluidic biochip with miniscule sample volume (&lt; 10 µL). The ClotChip readout was taken as the temporal variation in the real part of blood dielectric permittivity at 1 MHz. Our previous studies have shown that the ClotChip readout is sensitive to the global coagulation process and the time to reach a peak in permittivity (Tpeak) is a sensitive parameter to assess coagulation factor defects. Thrombin generation assay (TGA) using low tissue factor concentration was also performed on blood samples according to the manufacturer's direction. TGA was not available for 4 hemophilia and 2 control samples. Endogenous thrombin potential (ETP) parameter of TGA was used in this study to assess thrombin generation. Data are reported as mean ± standard deviation (SD). Analysis of variance (ANOVA) was used to test for statistical significance between groups with P &lt; 0.05. Spearman's correlation test was used to derive correlation statistics. Results: ClotChip exhibited a mean Tpeak of 2186s ± 1560s for hemophilia patients in the group with higher bleeding scores (i.e. score &gt;12), a mean Tpeak of 931s ± 496s for the group with lower bleeding scores (i.e. score &lt;12) and a mean Tpeak of 441s ± 74s for the healthy group (Figure 1A). A significant difference in Tpeak was found between the group with higher bleeding scores compared to the group with lower bleeding scores (P = 0.002) as well as between higher bleeding scores and the healthy group (P &lt; 0.0001). However, no significant difference in the TGA ETP parameter was detected between the groups with higher bleeding scores (mean ETP: 470 ± 814) and lower bleeding scores (mean ETP: 471 ± 897) (Figure 1B). ETP exhibited a statistical difference between the healthy group (mean ETP: 3462 ± 575) and both hemophilia groups (P &lt; 0.0001). We also carried out studies to investigate the correlative power of the ClotChip Tpeak parameter to the TGA ETP parameter when including additional blood samples that were collected at various times during a hemophilia patient's prophylaxis regimen. The ClotChip Tpeak parameter exhibited strong negative correlation to the TGA ETP parameter (Spearman's rs= -0.73, P &lt; 0.0001). Conclusions: Our studies suggest that a novel dielectric microsensor (ClotChip) could be useful in assessing bleeding phenotype in hemophilia A patients, allowing rapid assessment of hemostasis using a miniscule amount of whole blood (&lt;10 µL) at the POC. Further studies are needed to determine if ClotChip data can be used to individualize prophylactic factor replacement regimens in hemophilia A patients. Disclosures Maji: XaTek, Inc: Patents &amp; Royalties: 9,995,701. Suster:XaTek, Inc: Consultancy, Patents &amp; Royalties: 9,995,701. Mohseni:XaTek, Inc: Consultancy, Patents &amp; Royalties. Ahuja:XaTexk Inc.: Consultancy, Patents &amp; Royalties, Research Funding; Rainbow Children's Foundation: Research Funding; Bayer: Consultancy; Biovertiv Sanofi: Consultancy; Genentech: Consultancy.